Oxycodone/Ibuprofen Combination Tablet

Oxycodone/ibuprofen 5mg/400mg (Combunox™) is an oral fixed-dose combination tablet with analgesic, anti-inflammatory and antipyretic properties. It is approved in the US for the short-term (up to 7 days) management of acute, moderate-to-severe pain and is the first and only fixed-dose combination containing ibuprofen and oxycodone.

A single dose of oxycodone/ibuprofen 5mg/400mg provided better analgesia than low-dose oxycodone or ibuprofen administered alone in most trials and appears to be more effective than a single dose of some other fixed-dose combination analgesics. It is generally well tolerated after single or multiple doses and short-term use is not expected to produce any of the serious adverse effects typically associated with the long-term use of opioids or NSAIDs. Thus, oxycodone/ibuprofen 5mg/400mg is an effective, convenient treatment option for the short-term management of acute, moderate-to-severe pain.

An oral dose of oxycodone 5mg is rapidly absorbed, reaching a maximum plasma concentration (C_max) in 1–1.5 hours. The extent of oxycodone absorption is dose proportional. Oxycodone undergoes extensive hepatic metabolism to form the primary metabolites noroxycodone, the major circulating metabolite which also possesses weak antinociceptive activity, and oxymorphone, the formation of which is catalysed by cytochrome P450 (CYP) 2D6. Plasma clearance of oxycodone is reduced and plasma half-life is prolonged in patients with renal or hepatic insufficiency.

After administration of a single oral dose of ibuprofen 400mg, C_max (24.6 μg/ mL) is within the concentration range (11–30 μg/mL) that provided analgesia in 50% of patients in a dental pain model. Both (R)- and (S)-ibuprofen are extensively (>99%) bound to proteins in plasma. Ibuprofen is metabolised in the liver via oxidation (the primary metabolic route), inversion of (R) to (S)-ibuprofen, or glucuronidation. The metabolism and elimination of ibuprofen are impaired in patients with hepatic or renal insufficiency.

The pharmacokinetic properties of oxycodone and ibuprofen are not appreciably altered when they are administered as a fixed-dose combination of oxycodone/ ibuprofen 5mg/400mg. Compared with values observed after a single dose, the plasma concentration of oxycodone is increased after multiple 6-hourly doses of oxycodone/ibuprofen 5mg/400mg. Absorption of oxycodone from oxycodone/ ibuprofen 5mg/400mg is increased by ≈25% in the presence of food.

In randomised, double-blind, multicentre trials in patients aged ≥12 years with acute, moderate-to-severe pain after dental, abdominal or pelvic surgery, a single oral dose of oxycodone/ibuprofen 5mg/400mg provided significantly more effective analgesia than placebo. Oxycodone/ibuprofen recipients achieved higher mean scores than placebo recipients for total pain relief over 6 hours following administration of the study medication (TOTPAR6) and the sum of pain intensity differences from baseline (SPID6). Patients receiving oxycodone/ibuprofen were less likely to require rescue medication than placebo recipients and had a significantly longer time to remedication. Onset of pain relief was experienced by 90% of oxycodone/ibuprofen recipients compared with 36% of placebo recipients over the 6-hour postadministration period.

In the same well designed trials in patients with dental, abdominal or pelvic pain, oxycodone/ibuprofen provided more effective relief from acute, moderate-to-severe postoperative pain than oxycodone 5mg, oxycodone 10mg, oxycodone/ paracetamol (acetaminophen) 5mg/325mg, or hydrocodone/paracetamol 7.5mg/ 500mg in all studies and than ibuprofen 400mg in two of these studies. Oxycodone/ibuprofen recipients consistently reported significantly better TOTPAR6, SPID6 and global evaluation scores than recipients of comparator preparations, and significantly more oxycodone/ibuprofen recipients reported pain half gone at one hour or over the 6 hours after administration. The time to onset of pain relief (21 or 30 minutes) was significantly faster, and the duration of pain relief was significantly longer, with oxycodone/ibuprofen 5mg/400mg than with ibuprofen 400mg, oxycodone 5mg and hydrocodone/paracetamol 7.5mg/ 500mg.

Oxycodone/ibuprofen 5mg/400mg was generally well tolerated in patients aged ≥12 years with acute, moderate-to-severe postoperative pain. Nausea, dizziness and somnolence were the treatment-related adverse events that occurred most frequently after a single dose or multiple doses of oxycodone/ibuprofen. Most (52%) adverse events that occurred with multiple doses of oxycodone/ibuprofen were of mild severity.

Fewer patients receiving oxycodone/ibuprofen than those receiving oxycodone/paracetamol 5mg/325mg experienced nausea (6.5% vs 23%) or vomiting (3.2% vs 18%). The rate of withdrawal from treatment because of adverse events was low in patients receiving oxycodone/ibuprofen, and similar to that observed with placebo, oxycodone 5mg or ibuprofen 400mg. Patients who discontinued treatment with oxycodone/ibuprofen generally cited nausea and/or vomiting as the reasons for discontinuation.